Comparison between the Biological Active Compounds in Plants with Adaptogenic Properties (Rhaponticum carthamoides, Lepidium meyenii, Eleutherococcus senticosus and Panax ginseng)

Background: In the 1960s, research into plant adaptogens began. Plants with adaptogenic properties have rich phytochemical compositions and have been used by humanity since ancient times. However, it is not still clear whether the adaptogenic properties are because of specific compounds or because of the whole plant extracts. The aim of this review is to compare the bioactive compounds in the different parts of these plants. Methods: The search strategy was based on studies related to the isolation of bioactive compounds from Rhaponticum carthamoides, Lepidium meyenii, Eleutherococcus senticosus, and Panax ginseng. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Results: This review includes data from 259 articles. The phytochemicals isolated from Rhaponticum carthamoides, Lepidium meyenii, Eleutherococcus senticosus, and Panax ginseng were described and classified in several categories. Conclusions: Plant species have always played an important role in drug discovery because their effectiveness is based on the hundreds of years of experience with folk medicine in different nations. In our view, there is great potential in the near future for some of the phytochemicals found in these plants species to become pharmaceutical agents.

The structure-activity relationship of ecdisteroids is still not well clarified. Some researchers suggest that the presence of hydroxyl groups on C-5, C-14, and C-22 positions is very important for the biological activity of these compounds as well the presence of double bond at C-7 and keto-group at C-6 (example: ecdisterone) [57][58][59]. The presence of 2,3-diol system, hydroxyl group at C-20 in ecdysteroids structures is important for the anabolic activity [60].
In the near future, it is highly likely that ecdysterone will become a drug molecule, used for obesity management, reducing fatigue or the management of glucose levels. It is also highly likely to be included in WADA's prohibited list if researchers prove it has the potential to improve athletes' performance. However, its biological activity should be studied in more detail in cell cultures and mammals, and in randomized clinical trials.
Rhaponthicum carthamoides is also a source of flavonoids, which are mainly found in the roots and leaves [24,25]. Flavonoids are substances with a phenolic structure, and over 8000 flavonoids are known [80,81]. Flavonoids are divided into the subclasses flavonols, flavones, flavanones, catechins, and their glycosides [25]. The presence of flavonoids in Rhaponticum carthamoides extracts determines the hypolipidemic and antioxidative effects of the extract [81,82]. Antioxidant activity is associated with the presence of a large number of hydroxyl groups in flavonoids [83].
Although the root is the main part used for the preparation of Rhaponthicum carthamoides extracts, other parts of the plant also have a rich phytochemical composition.  Although the root is the main part used for the preparation of Rhaponthicum carthamoides extracts, other parts of the plant also have a rich phytochemical composition.
Maca is a perennial plant. Its overground part consists of 12-20 basal frost-hardy leaves forming a rosette, the height of which can reach 20 cm [98,110,111]. Its flowers are whitish with a length of 5 mm [98]. The fruits are two-celled [98]. The seeds are smooth and reddish with an ovoid shape [98]. The underground part-the tuber-is composed of roots and seedling stems (hypocotyl) [98,[110][111][112]. The tuber color varies from white to purple; its size is usually about 10-14 cm, with different shapes [98,110,111]. The weight of the Maca tuber varies from 1 to 5 kg [111].
Several studies involving animals have investigated the Maca extract's biological activity, and reported some beneficial effects such as improvement of memory and cognitive functions, neuroprotective effects, regulation of sexual hormones and spermatogenesis, antioxidant activity, and improvement of lipide and glucose profiles [131][132][133][134][135][136][137]. Studies involving humans are limited. However, the data provided by these trials suggest beneficial effects of Maca extract in postmenopausal women, with the management of sexual functions and mood regulation [138][139][140][141].

Nutritional Ingredients Isolated from Maca
Lepidium meyenii contains some essential nutrients, such as amino acids, fibers, acids, lipids, proteins, and minerals [18,22]. Because of its unique nutritional and p chemical composition, Maca is considered a "super food" [95,111,153]. Different Mac tracts, such as the tuber and starch, are used as food [154][155][156]. The term "super fo includes products that are used as foods and medicine, which are edible [153]. In th few decades, research into superfoods has increased [157]. Super foods may contain c ical-free proteins, amino acids, fatty acids, vitamins, minerals, polysaccharides, and natural ingredients [158]. The intake of super foods provides essential nutrients and oxidants, and it also supports the immune system, the endocrine system, and the ca vascular system [159]. The most important nutrients from in Lepidium meyenii ar scribed in Table 3.

Nutritional Ingredients Isolated from Maca
Lepidium meyenii contains some essential nutrients, such as amino acids, fibers, fatty acids, lipids, proteins, and minerals [18,22]. Because of its unique nutritional and phytochemical composition, Maca is considered a "super food" [95,111,153]. Different Maca extracts, such as the tuber and starch, are used as food [154][155][156]. The term "super foods" includes products that are used as foods and medicine, which are edible [153]. In the last few decades, research into superfoods has increased [157]. Super foods may contain chemical-free proteins, amino acids, fatty acids, vitamins, minerals, polysaccharides, and other natural ingredients [158]. The intake of super foods provides essential nutrients and antioxidants, and it also supports the immune system, the endocrine system, and the cardiovascular system [159]. The most important nutrients from in Lepidium meyenii are described in Table 3.

Eleutherococcus senticosus
Eleutherococcus senticosus (Araliaceae) is a small, woody shrub, known also as "Siberian ginseng", which naturally grows in East Russia, Korea, China, and Japan [12,160]. It is a perennial plant and an important herb in Eastern folk medicine [12,161].
Nowadays, Eleutherococcus senticosus rhizome and radices are also considered especially valuable, and are included in the European and Russian pharmacopoeias [34,162].
The knotty Eleutherococcus senticosus rhizome has a diameter of 4.0 cm with an irregular cylindrical shape. The bark thickness is 2 mm with a greyish brown to blackish-brown color. The roots can be up to 15 cm in length with a diameter of 0.3 to 1.5 cm [162].
Although all parts of this plant have rich phytochemical compositions, the roots are the most utilized. Roots are used in the form of liquid extracts, powders, etc. [160,175]. According to data from human studies, Eleutherococcus senticosus extract has the potential to improve oxygen consumption, mental health, lipid, and glycemic profile [167,168,176,177]. Data obtained from animal studies suggests antidiabetic, antifatigue, neuroprotective, and nootropic activity [171,172,178,179].
The molecules isolated from Eleutherococcus senticosus with the greatest potential to become novel drug molecules are Eleutheroside B and Eleutheroside E.

Panax ginseng
Panax ginseng has always been considered an important medicinal plant. Initially, it was an important part of Eastern folk medicine, and nowadays it is an essential pharmacopeial plant. Furthermore, in the past it was considered the most valuable of all medicinal herbs for the people of Korea, China, and Japan [195].
Brekhman was among the first researchers to introduce the novel pharmacological concept of the tonic effect of ginseng, resulting in the association of the plant with adaptogen effects [195].
Brekhman found out ginseng intake can increase non-specific resistance to various pathological or stress factors. According to his findings, the adaptogenic effect lasts for a long time, and work better under abnormal conditions (stress factors) [4,195,196].
Panax ginseng naturally grows in Korea and China [197,198]. The genus name "Panax" originates from Greek. The word is composed of the words "pan", which means "all", and "axos", which means "treat". The literal translation is "cure all diseases", "cure everything" or "appropriate for treatment of every condition" [195]. The word "ginseng" has an Eastern origin [195]. It is a perennial, self-pollinating plant. It has one stalk and palmate leaves at its end. The flowering starts in its third-year growth stage. Panax ginseng seeds are obtained from plants no less than four years old. Panax ginseng roots may be white or pale yellow, and grow upright. There is one stout primary root and two or five rootlets and root hairs. The size and shape of the rootlets depends on water content, soil quality, weather, and other factors. Ginseng roots are considered most valuable between 4 and 6 years of age. Roots younger than 4 years are considered immature, and should not be used for medical purposes [195].
Panax ginseng radix is included in the European pharmacopoeia [199]. According to the European pharmacopeia, the root should have a cylindrical or fusiform shape with a length of 20 cm and a 2.5 cm diameter. The root surface should be pale yellow to brownishred [199].

Phytochemicals Isolated from Eleutherococcus senticosus Stem and Leaves
The main bioactive compounds are eleutheroside B, with an average concentration of 0.1203%, and eleutheroside E, with an average concentration of 0.085% [187]. Chiisanoside, hyperin, and triterpene glycosides, such as inermoside, 24-hydroxychiisanoside and 11deoxyisochiisanoside, are the main phytochemical compounds isolated from Eleutherococcus senticosus leaves [192,193].

Panax ginseng
Panax ginseng has always been considered an important medicinal plant. Initially, it was an important part of Eastern folk medicine, and nowadays it is an essential pharmacopeial plant. Furthermore, in the past it was considered the most valuable of all medicinal herbs for the people of Korea, China, and Japan [195].
Brekhman was among the first researchers to introduce the novel pharmacological concept of the tonic effect of ginseng, resulting in the association of the plant with adaptogen effects [195].
Brekhman found out ginseng intake can increase non-specific resistance to various pathological or stress factors. According to his findings, the adaptogenic effect lasts for a long time, and work better under abnormal conditions (stress factors) [4,195,196].
Panax ginseng naturally grows in Korea and China [197,198]. The genus name "Panax" originates from Greek. The word is composed of the words "pan", which means "all", and "axos", which means "treat". The literal translation is "cure all diseases", "cure everything" or "appropriate for treatment of every condition" [195]. The word "ginseng" has an Eastern origin [195]. It is a perennial, self-pollinating plant. It has one stalk and palmate leaves at its end. The flowering starts in its third-year growth stage. Panax ginseng seeds are obtained from plants no less than four years old. Panax ginseng roots may be white or pale yellow, and grow upright. There is one stout primary root and two or five rootlets and root hairs. The size and shape of the rootlets depends on water content, soil quality, weather, and other factors. Ginseng roots are considered most valuable between 4 and 6 years of age. Roots younger than 4 years are considered immature, and should not be used for medical purposes [195].
Panax ginseng radix is included in the European pharmacopoeia [199]. According to the European pharmacopeia, the root should have a cylindrical or fusiform shape with a length of 20 cm and a 2.5 cm diameter. The root surface should be pale yellow to brownish-red [199].
The main active ingredients in Panax ginseng are saponins, also known as ginsenosides [201]. They include tetracyclic triterpenoid saponins of the dammarane type (four-ring carbon skeleton) and oleanane type (five-ring carbon skeleton) [198,201,202,207,208]. They consist of gonane, with 17 carbon atoms arranged in four rings [209]. Over 30 ginsenosides have been isolated from Panax [210]. It is considered that ginsenosides are responsible for the adaptogenic properties of Panax ginseng [198]. Other well-known effects of ginsenosides are related to anti-inflammatory activity, neuroprotective activity, antidiabetic effects, nootropic activity, and many other factors [207,211,212]. The variety of these activities of ginsenosides is based on the quantity and the positions of hydroxyl groups [213]. Ginsenosides can be isolated not only from Panax ginseng, but also from all of Panax species, such as Panax quinquefolius L., Panax notoginseng (Burkill) F. H. Chen, Panax japonicas (T. Nees) C. A. Mey. and Panax zingiberensis C. Y. Wu and K. M. Feng [207,[214][215][216].
According to studies involving humans, ginsenosides may improve calmness, mental health, and the overall quality of life. Moreover, their intake is associated with antihyperlipidemic, antidiabetic, and anti-fatigue effects [203,206,[217][218][219][220]. The data obtained from animal studies suggest that ginsenosides could be included in the management of diabetes and cardiovascular diseases, in the treatment of impaired immunity, or could be used as hepatoprotectors [203,[221][222][223][224][225][226].
Although Panax ginseng is a source of plenty of biological active compounds, the molecules with the greatest potential to become drug molecules are ginsenosides. According to data obtained from animal studies, ginsenosides have great potential to be used for the treatment of cardiovascular diseases, hepatic disorders and obesity [227][228][229][230][231][232][233]. According to data obtained from cell culture studies, ginsenosides have great potential to be used for the treatment cardiovascular diseases, hypercholesterolemia, and some types of cancer [234][235][236][237]. Table 5 shows the isolated bioactive compounds from Panax ginseng. Table 5. Bioactive compounds in Panax ginseng.

Comparison between Rhaponticum carthamoides, Lepidium meyenii, Eleutherococcus senticosus and Panax ginseng and Future Perspectives
Bioactive compounds and their concentration isolated from plants are not constant. For example, the content of the phytochemicals varies in different parts of the species and also depends on many factors like soil, soil management, climate, and pollutants [55,187,[256][257][258].
For that reason, it is very important the feature research about these plants to be focused mostly on their active molecules that to the whole extracts. However, comparison between the biological activity of the extracts and the active molecules would provide valuable data.
Although the four plants have quite different phytochemical composition (Table 6), the future perspectives for introduction of their specific molecules/ plant extracts as medi-cines are similar [12,13,22,23]. Most of them could be included in the management of dia-betes, cardiovascular diseases, or used as nootropic agents and hepatoprotectors (Table 7) [12,18,35,62,67,132]. Rhaponticum carthamoides is the only plant among these which has the greatest potential to be used as a remedy for improvement physical performance, because of potential ergogenic activity. Ecdysterone, which is one of its active compounds is in process of monitoring by WADA as a doping compound [65]. Moreover, in near future the extract or its active compounds could be applied for obesity/ overweight management [259,260].  In term to establish the biological activity of Rhaponticum carthamoides, Lepidium meyenii, Eleutherococcus senticosus, Panax ginseng/their active compounds, cell cultures research would be especially useful to give the right direction for future investigations.

Conclusions
Plants have always played an important role in drug discovery, and their effectiveness is based on hundreds of years' experience in the folk medicines of different nations. In the 1960s, the first plants with adaptogenic activities were described: Rhaponticum carthamoides, Eleutherococcus senticosus, and Panax ginseng. Later, Lepidium meyenii was also included in the plant adaptogens family.
The main phytochemicals isolated from these plants are phytosteroids, phytosterols, alkaloids, and saponins. These biologically active compounds determine the therapeutic effects of plants not only as adaptogens, but also as antioxidants, hepatoprotectors, immunomodulators, hormone regulators, and others. Plants have always been an important source of past and novel drug molecules. In our view, there is great potential for some of the phytochemicals found in these plant species, such as ginsenosides, ecdysterone, macamides, macaenes, and eleutherosides to become novel drug molecules. However, their biological activity should be studied in more detail in cell cultures, in mammals, and in randomized clinical trials.